Influence of the N-Methyl-D-Aspartate Receptor coagonist, D-Cycloserine, on Memory Consolidation and subsequent Learning under Sleep Deprivation

Abstract

Synaptic plasticity, specifically long-term potentiation (LTP) and long-term depression (LTD), are well-established correlates of memory processes. The manipulation of NMDA receptors, which are critically involved in these forms of synaptic plasticity, offer a promising and thus frequently used means to gain new insight into the mechanisms of memory. Here, I investigated if the application of the NMDA receptor coagonist d-cycloserine (DCS) during consolidation affected subsequent learning in a sleep deprivation setting. To this end I administered DCS (vs. placebo) shortly after an initial word pair association task and measured the effect on subsequent learning of a similar task after DCS had reached negligible plasma levels. Assessing the indirect DCS effect on subsequent learning, allows to infer the effect of DCS on consolidation of the initial task. I hypothesised that enhanced or reduced subsequent learning performance would result from enhanced or reduced proactive interference from the initial memory task. In the current study subsequent learning was enhanced by DCS, suggesting decreased proactive interference. Such decreased interference could be brought about if DCS enhanced LTD. A related, methodologically identical study found similarly enhanced new learning under normal sleep settings. Together, this suggests that the LTD-enhancing effect of DCS is independent of the behavioural state (sleep vs wake). By contrast, an earlier study suggests that recall performance of the initial memory task is enhanced by DCS sleep dependently. Taken together these studies show the interesting pattern of sleep dependent enhancement of consolidation and sleep independent enhancement of subsequent learning. A possible explanation is, that DCS enhanced LTD, supporting homeostatic synaptic downregulation and thereby diminishing proactive interference with the subsequent task, independent of the behavioural state. In contrast, DCS induced enhancement of LTP may rely on sleep dependent processes, such as sleep dependent synaptic reactivations during active system consolidation. This is in line with previous studies and accounts suggesting that NMDA receptor activation has the potential to induce LTP and LTD, respectively, and that the direction of long term plasticity is in part dependent on the previous activity of the respective synapses.

The data presented in this work together with the data of the related sleep study have been published in: Alizadeh Asfestani, M., Braganza E., Schwidetzky, J., Santiago, J., Soekadar, S., Born, J. & Feld, G. 2018. Overnight memory consolidation facilitates rather than interferes with new learning of similar materials – a study probing NMDA receptors. Neuropsychopharmacology, 43, 2292 – 2298.